Drug Targeting Organ-Specific Strategies

352 13 Pharmacokinetic/Pharmacodynamic Modelling in Drug Targeting
eliminating organs to the targeted drug (in the case of release or activation of the drug in the
eliminating organs) and to maximize the therapeutic availability, that is, to maximize the fraction
of the dose that reaches the target site. Ideally, the elimination of the DC should take
place exclusively in the target organ (see Sections 13.3.1.2 and 13.3.1.3). Elimination at other
sites reduces the efficiency of targeting. For example, elimination of the DC without release
of the active drug implies a waste of a sophisticated and expensive product, and elimination
of the DC with release of active drug in non-target tissue increases the concentration of D in
non-target tissue, thus lowering the Drug Targeting Index (DTI, see Section 13.4.2) [12].
In general, optimization of the disposition of DC is the simplest part of the design of a drug
targeting system. There are many methods by which the retention time of the drug carrier
within the target tissue can be prolonged (described in other chapters of this book), and
the assessment of the disposition of the DC by measuring its plasma or blood concentration–time
profile is relatively simple.
13.3.1.2 Delivery of the DC to the Target Site
The focus of research in the field of drug targeting is mainly on the selectivity of the DC for
the target site (see other chapters in this book), undoubtedly because it is the essential
process in drug targeting.
Although the delivery of the DC to the target site is a critical step in the efficacy of drug
targeting, it is not necessarily the most critical step. In fact, each of the processes involved
may be critical, and it is possible that in practice, given the sophisticated principles which are
applied to increase the selectivity of DC for the target site, one of the other processes involved
(see Sections 13.3.1.1. and 13.3.1.3.6) is responsible for the eventual failures of drug
targeting systems.
The general principles of drug transport have been described in Sections 13.2.1.2 and
13.2.1.3.The rate of delivery of the DC to the target site is not critical in absolute terms. Even
if the delivery rate is low, as long as the selectivity of the DC for the target site is high efficient
targeting is assured. In this case, it will take more time to reach effective steady-state
drug levels in the target organ and the duration of the drug effect will be prolonged. However,
if the selectivity of DC for the target site is less than 100%, the slow delivery of the DC to
the target site may decrease the efficacy of drug targeting [12].
If the rate of delivery of the DC to the target site is high compared to the release of the activated
drug (see Section 13.3.1.3), accumulation of DC at the target site might result in a loss
of DC from the target site either back into the blood, or via lymphatic drainage, and thus in
a decrease of the efficiency of targeting. An example of this is the occurrence of retro-endocytosis
in which the endocytosed DC is refluxed back into the systemic circulation before it
has released the drug to be targeted [41]. The possibility that receptor-mediated endocytosis
is a bidirectional rather than a unidirectional process is often not taken into account in drug
targeting models. Yet, a secondary release of endocytosed material through reactivation of
endocytotic vesicles in the plasma membrane has been demonstrated in various cell types.
This process may be of quantitative importance, especially if trafficking to and association
with lysosomes is slow or if proteolytic degradation is rate-limiting.